Oxaliplatin is an active agent in metastatic colorectal cancer regimens, but most patients either fail to respond to 5-FU and oxaliplatin (FOLFOX) combinations or subsequently develop resistance. A candidate molecule that might contribute to oxaliplatin resistance is the protein tyrosine kinase, Src, the activity of which is increased during colorectal tumor progression and highest in metastatic disease. Our preliminary studies demonstrate that Src is activated in colon cancer cell lines after oxaliplatin treatment in vitro and in vivo. We have shown that inhibition of Src by siRNA increases sensitivity to oxaliplatin. Likewise, pharmacologic inhibition of Src with dasatinib, an oral tyrosine kinase inhibitor, is synergistic with oxaliplatin in vitro and demonstrates at least supra-additive reductions in tumor size in an orthotopic murine model. These findings lead to the following hypothesis to be tested in this proposal: Src activation resulting from oxaliplatin treatment is a pro-survival mechanism and inhibition of Src will therefore improve oxaliplatin cytotoxicity in metastatic colorectal cancer. Specific aim 1 is to determine if constitutive Src activation is sufficient to induce oxaliplatin resistance in both cell cultures and an orthotopic nude mouse model of colorectal liver metastases by molecular approaches to develop colorectal tumor cell lines in which Src activity cannot be regulated. These studies will use transfected Src with a point mutation rendering Src constitutively active, thereby allowing evaluation of oxaliplatin sensitivity and the subsequent impact of dasatinib therapy. Specific aim 2 is to determine the frequency of Src activation in liver metastases after oxaliplatin treatment in colorectal patients undergoing liver metastasectomy in order to demonstrate the clinical relevance of these preclinical findings. Specific aim 3 is designed to evaluate the safety, preliminary efficacy, and pharmacodynamics of the combination of dasatinib and FOLFOX + cetuximab in patients with metastatic colorectal cancer. This investigator-initiated study, to which we have recently initiated accrual, includes extensive correlative studies to demonstrate inhibition of Src and Src targets in the tumor. Specific aim 4 further evaluates the efficacy of this regimen in a Bayesian adaptively randomized, placebo-controlled phase II study of FOLFOX + cetuximab +/- dasatinib, with concurrent evaluation of a biomarker of Src inhibition. Successful implementation will improve the effectiveness of current chemotherapies for metastatic colorectal cancer, resulting in improved outcomes for the metastatic colorectal cancer population.